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CombiGyrase


Development of new gyrase inhibitors by combinatorial biosynthesis
EC contribution
: € 1.555.415
Duration
: 36 months
Starting date
: 01/01/2004
Funding scheme
: Specific Targeted Research Project
Keywords
: antibiotics, resistance, anti-infective, gyrase, aminocoumarin, simocyclionone
Contract/Grant agreement number
: 503466
Project web-site
: -

Background:

The bacterial enzyme DNA gyrase is well validated as a target for a number of antibacterial compounds. The CombiGyrase consortium took advantage of the expertise that existed across Europe to research and develop new drugs that are urgently needed. It represented an ideal platform to expand the diversity of potent gyrase inhibitors found in nature by methods of combinatorial biosynthesis. Combinatorial biosynthesis is a novel technology that uses genetic manipulation to improve the chemical properties and pharmacological activity of naturally occurring compounds. Using microorganisms which produce natural gyrase-inhibiting antibiotics, the CombiGyrase consortium successfully demonstrated that novel 'designer' antibiotics can be developed by combinatorial genetic methods. New gyrase-directed drugs, such as aminocoumarin and simocyclinone antibiotics, developed by these methods, may help to overcome problems due to clinical resistance, and may significantly expand the clinical role of the gyrase inhibitors as antibacterial agents.


Problem:

A constant threat to the population of the European Community is the ever-increasing problem of antibiotic resistance. Widespread use of antibiotics has led to the emergence of antibiotic-resistant strains. The increase and spread of resistance are a matter of serious public health concern worldwide. For example, vancomycin has long been considered as the solution to methicillin-resistant Staphylococcus aureus (MRSA) infections, but vancomycin-resistant strains of S. aureus have already begun to emerge. Nowadays, the risk of infection increases with a prolonged hospital stay, and so does failure of antibiotic therapy because of multidrug resistance.

In the last decade, many pharmaceutical companies have reduced their efforts to discover new anti-infectives, particularly new antibiotics, and redirected their R&D efforts to other fields perceived as more profitable. However, infectious diseases represent a large market with high unmet medical needs, as shown by the strong interest of many large pharmaceutical companies to acquire novel antibiotics once they have reached late development/registration stages.

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